Valproate and palmitate binding to human serum albumin: an hypothesis on obesity.
Valproate and palmitate binding to human serum albumin: an hypothesis on obesity.
复制标题
丙戊酸和棕榈酸与人血清白蛋白的结合：关于肥胖的假设。
作者：
R. Brodersen;N. Jørgensen;H. Vorum;N. Krukow
在66 mM磷酸钠缓冲液（pH 7.4，37 ℃）中，通过平衡透析研究了丙戊酸盐（2-正丙基戊酸阴离子）与脱脂人血清白蛋白的结合平衡。获得了结合与游离丙戊酸盐浓度的300五十六个观察点，并根据逐步结合进行了分析。发现最佳拟合来自一个模型，其中67%的白蛋白能够结合丙戊酸盐，而33%的白蛋白不能结合。生成30个可接受的曲线拟合变体，以评估结合常数的变化。结合白蛋白组分与3个高亲和力丙戊酸盐分子结合，并与至少7个松散结合的其他分子结合。不能达到蛋白质的饱和。在极高浓度的游离丙戊酸盐（高于10 mM）下，白蛋白发生不可逆变化，导致丙戊酸盐结合量的重现性较差。在存在棕榈酸盐、0.5、1和1.5 mol/mol白蛋白的情况下，丙戊酸盐的结合通过竞争性机制降低。据推测，肥胖是丙戊酸盐治疗癫痫的并发症，是由于丙戊酸盐竞争性结合导致长链脂肪酸可用性增加所致。
Binding equilibria of valproate (2-n-propyl-pentanoic acid anion) with defatted human serum albumin were studied by equilibrium dialysis in a 66 mM sodium phosphate buffer, pH 7.4, 37 degrees. Three hundred and fifty-six observed points for bound versus free valproate concentration were obtained and analyzed in terms of stepwise binding. It was found that the best fit resulted from a model in which 67% of the albumin was capable of binding valproate, whereas 33% did not bind. Thirty acceptable variants of the curve fitting were generated in order to assess the variation of the binding constants. The binding albumin component combines with three molecules of valproate with high affinity and with at least seven additional molecules that are loosely bound. Saturation of the protein cannot be reached. At very high concentrations of free valproate (above 10 mM) irreversible changes in the albumin take place, resulting in poor reproducibility in the amount of bound valproate. In the presence of palmitate, 0.5, 1, and 1.5 mol/mol of albumin, binding of valproate is decreased by a competitive mechanism. It is hypothesized that obesity, developing as a complication of valproate treatment of epilepsy, results from increased availability of long-chain fatty acids due to competitive valproate binding.